Treatment of intrahepatic cholestatic diseases

ABSTRACT

Treatment of intrahepatic cholestatic diseases by therapy with seladelpar or a salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 16/676,014,filed 6 Nov. 2019 and now allowed; which is a continuation ofapplication Ser. No. 16/032,380, filed 11 Jul. 2018 and now U.S. Pat.No. 10,512,622; both entitled “Treatment of intrahepatic cholestaticdiseases”. Application Ser. No. 16/032,380 claims the priority under 35USC 119(e) of Applications Nos. 62/532,571, filed 14 Jul. 2017, and62/563,491, filed 26 Sep. 2017, both entitled “Treatment of intrahepaticcholestatic diseases”. The entire disclosures of both of thoseprovisional applications have been incorporated into application Ser.No. 16/032,380 by reference.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to the treatment of intrahepatic cholestaticdiseases.

Description of the Related Art

Intrahepatic Cholestatic Diseases

Cholestasis is a condition in which the flow of bile from the liver tothe duodenum is slowed or blocked. Cholestasis may be dividedconveniently into two types: intrahepatic cholestasis, inside the liver,where bile formation is disturbed by conditions such as variousdiseases, extended intravenous nutrition, or as a side effect of certaindrugs (such as some antibiotics); and extrahepatic cholestasis,occurring outside the liver, typically where the flow of bile isobstructed by a mechanical partial or complete closure of the bile duct,such as by bile duct tumors, cysts, bile duct stones, strictures, orpressure on the bile duct; though primary sclerosing cholangitis (PSC)may be intrahepatic or extrahepatic. Common symptoms of cholestasisinclude fatigue, pruritus (itching), jaundice, and xanthoma (deposits ofcholesterol-rich material under the skin). The effects of cholestasisare profound and widespread, leading to worsening liver disease withsystemic illness, liver failure, and the need for liver transplantation.

Intrahepatic cholestatic diseases include, in order of decreasingfrequency, primary biliary cholangitis (PBC, formerly known as primarybiliary cirrhosis), primary sclerosing cholangitis (PSC), progressivefamilial intrahepatic cholestasis (PFIC), and Alagille syndrome (AS).

PBC is an autoimmune disease of the liver marked by the slow progressivedestruction of the small bile ducts of the liver, with the intralobularducts affected early in the disease. When these ducts are damaged, bilebuilds up in the liver (cholestasis) and over time damages the tissue,which can lead to scarring, fibrosis and cirrhosis. Recent studies haveshown that it may affect up to 1 in 3,000-4,000 people, with a sex ratioat least 9:1 female to male. There is no cure for PBC, and livertransplantation often becomes necessary; but medication such asursodeoxycholic acid (UDCA, ursodiol) to reduce cholestasis and improveliver function, cholestyramine to absorb bile acids, modafinil forfatigue, and fat-soluble vitamins (vitamins A, D, E, and K, sincereduced bile flow makes it difficult for these vitamins to be absorbed)may slow the progression to allow a normal lifespan and quality of life.UDCA is approved in the United States to treat PBC. Japanese researchershave reported that the addition of bezafibrate, a peroxisomeproliferator-activated receptor (PPAR) pan-agonist and pregnane Xreceptor agonist, to UDCA is helpful in treating patients who arerefractory to UDCA monotherapy, improving serum biliary enzymes,cholesterol (C), and triglycerides (TGs). Obeticholic acid (OCA,6α-ethylchenodeoxycholic acid), a semi-synthetic bile acid analog thatis a highly potent farnesoid X receptor agonist, was approved in 2016 inthe United States for the treatment of PBC, either in addition to UDCAor as sole treatment when UDCA is not tolerated.

PSC is a chronic cholestatic liver disease characterized by intra- orextrahepatic biliary duct inflammation and fibrosis, eventually leadingto cirrhosis. The underlying cause of the inflammation is believed to beautoimmunity; and about three-fourths of patients with PSC haveinflammatory bowel disease, usually ulcerative colitis, though this isreported to vary by country, as is the prevalence (generally reported atabout 1 in 10,000) and sex ratio (generally reported as predominatelymale). Standard treatment includes UDCA, which has been shown to lowerelevated liver enzyme numbers in people with PSC, but has not improvedliver survival or overall survival; and also includes antipruritics,cholestyramine, fat-soluble vitamins, and antibiotics to treatinfections (bacterial cholangitis). In a study reported in 2009,long-term high-dose UDCA therapy was associated with improvement inserum liver tests in PSC but did not improve survival and was associatedwith higher rates of serious adverse events. Liver transplantation isthe only proven long-term treatment.

PFIC refers to a group of three types of autosomal recessive disordersof childhood associated with intrahepatic cholestasis: deficiency offamilial intrahepatic cholestasis 1 (PFIC-1), deficiency of bile saltexport pump (PFIC-2), and deficiency of multidrug resistance protein 3(PFIC-3). They have a combined incidence of 1 in 50,000-100,000. Theonset of the disease is usually before age 2, with PFIC-3 usuallyappearing earliest, but patients have been diagnosed with PFIC even intoadolescence. Patients usually show cholestasis, jaundice, and failure tothrive; and intense pruritus is characteristic. Fat malabsorption andfat-soluble vitamin deficiency may appear. Biochemical markers include anormal γ-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, but amarkedly elevated GGT in PFIC-3; while serum bile acid levels aregreatly elevated; though serum cholesterol levels are typically notelevated, as is seen usually in cholestasis, because the disease is dueto a transporter as opposed to an anatomical problem with biliary cells.The disease is typically progressive without liver transplantation,leading to liver failure and death in childhood; and hepatocellularcarcinoma may develop in PFIC-2 at a very early age. Medication withUDCA is common; supplemented by fat-soluble vitamins, cholestyramine,and pancreatic enzymes in PFIC-1.

AS, also known as Alagille-Watson syndrome, syndromic bile duct paucity,and arteriohepatic dysplasia, is an autosomal dominant disorderassociated with liver, heart, eye and skeletal abnormalities, as well ascharacteristic facial features; with an incidence of about 1 in 100,000.The liver abnormalities are narrowed and malformed bile ducts within theliver; and these result in obstruction of bile flow, causing cirrhosis(scarring) of the liver. AS is predominately caused by changes in theJagged1 gene, located on chromosome 20. In 3-5% of cases, the entiregene is deleted (missing) from one copy of chromosome 20; in theremainder, there are changes or mutations in the Jagged1 DNA sequence.In a very small number of cases, less than 1 percent, changes in anothergene, Notch2, result in AS. In about one-third of the cases, themutation is inherited; in about two-thirds, the mutation is new in thatcase. There is no cure for AS, though the severity of liver diseasetypically peaks by 3 to 5 years of age and often resolves by 7 to 8years of age. In some people, the hepatic disease will progress toend-stage liver disease and may require liver transplantation;approximately 15% of patients with AS require liver transplantation. Anumber of different medications, for example UDCA, have been used toimprove bile flow and reduce itching, and many patients are given highdoses of fat-soluble vitamins.

Alkaline phosphatase (ALP) and GGT are key markers of cholestasis. Whilean elevation of one of them alone does not indicate cholestasis, andother parameters would be needed for confirmation, elevation in both ALPand GGT is indicative of cholestasis; and a decrease in both indicatesimprovement of cholestasis. Thus ALP and GGT levels serve as biochemicalmarkers for the presence of biliary pathophysiology present inintrahepatic cholestatic diseases, and ALP level has been used as aprimary outcome marker in clinical studies of intrahepatic diseases suchas PBC (including in the studies leading to US approval of OCA).

Treatments for Intrahepatic Cholestatic Diseases

As mentioned above, UDCA is a common treatment for intrahepaticcholestatic diseases, because of its action in reducing cholestasis andimproving liver function. However, a Cochrane Review of UDCA in PBC in2012 found that, although UDCA showed a reduction in biomarkers of liverpathology, jaundice, and ascites, there was no evidence in the medicalliterature for any benefit of UDCA on mortality or livertransplantation, while its use was associated with weight gain andcosts. Also, as mentioned above, OCA was approved in 2016 in the UnitedStates for the treatment of PBC, either in addition to UDCA or as soletreatment when UDCA is not tolerated. While UDCA is also used in otherintrahepatic cholestatic diseases, the only long-term treatment for manypatients with intrahepatic cholestatic diseases is livertransplantation.

It would be desirable to develop pharmacological treatments forintrahepatic cholestatic diseases.

Seladelpar

Seladelpar (International Nonproprietary Name—INN) has the chemical name[4-({(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl}sulfanyl)-2-methylphenoxy] acetic acid [IUPAC name from WHO RecommendedINN: List 77], and the code number MBX-8025. Seladelpar and itssynthesis, formulation, and use are disclosed in, for example, U.S. Pat.No. 7,301,050 (compound 15 in Table 1, Example M, claim 49), U.S. Pat.No. 7,635,718 (compound 15 in Table 1, Example M), and U.S. Pat. No.8,106,095 (compound 15 in Table 1, Example M, claim 14). Lysine(L-lysine) salts of seladelpar and related compounds are disclosed inU.S. Pat. No. 7,709,682 (seladelpar L-lysine salt throughout theExamples, crystalline forms claimed).

Seladelpar is an orally active, potent (2 nM) agonist of peroxisomeproliferator-activated receptor-δ (PPARδ). It is specific (>600-foldand >2500-fold compared with PPARα and PPARγ receptors). PPARδactivation stimulates fatty acid oxidation and utilization, improvesplasma lipid and lipoprotein metabolism, glucose utilization, andmitochondrial respiration, and preserves stem cell homeostasis.According to U.S. Pat. No. 7,301,050, PPARδ agonists, such asseladelpar, are suggested to treat PPARδ-mediated conditions, including“diabetes, cardiovascular diseases, Metabolic X syndrome,hypercholesterolemia, hypo-high density lipoprotein(HDL)-cholesterolemia, hyper-low density protein (LDL)-cholesterolemia,dyslipidemia, atherosclerosis, and obesity”, with dyslipidemia said toinclude hypertriglyceridemia and mixed hyperlipidemia.

A Phase 2 study of seladelpar L-lysine dihydrate salt in mixeddyslipidemia (6 groups, 30 subjects/group: once daily oral placebo,atorvastatin (ATV) 20 mg, or seladelpar L-lysine dihydrate salt at 50 or100 mg (calculated as the free acid) capsules alone or combined with ATV20 mg, for 8 weeks) has been reported by Bays et al., “MBX-8025, A NovelPeroxisome Proliferator Receptor-δ Agonist: Lipid and Other MetabolicEffects in Dyslipidemic Overweight Patients Treated with and withoutAtorvastatin”, J. Clin. Endocrin. Metab., 96(9), 2889-2897 (2011) andChoi et al., “Effects of the PPAR-δ agonist MBX-8025 on atherogenicdyslipidemia”, Atherosclerosis, 220, 470-476 (2012). Compared toplacebo, seladelpar alone and in combination with ATV significantly(P<0.05) reduced apolipoprotein B-100 by 20-38%, LDL by 18-43%,triglycerides (TGs) by 26-30%, non-HDL-C by 18-41%, free fatty acids by16-28%, and high-sensitivity C-reactive protein (hs-CRP) by 43-72%; itraised HDL-C by 1-12% and also reduced the number of patients with themetabolic syndrome and a preponderance of small LDL particles.Seladelpar significantly reduced ALP by 32-43%, compared to reductionsof only 4% in the control group and 6% in the ATV group; andsignificantly reduced GGT by 24-28%, compared to a reduction of only 3%in the control group and an increase of 2% in the ATV group.

US Patent Application Publication No. US 2015/0265560 A1 and PCTInternational Publication No. WO 2015/143178 A1 disclose the treatmentof intrahepatic cholestatic diseases, such as PBC, PSC, PFIC, and ASwith seladelpar; and US Patent Application Publication No. US2017/0340589 A1 and PCT International Publication No. WO 2017/209865 A1disclose the treatment of intrahepatic cholestatic diseases, such asPBC, PSC, PFIC, and AS with low doses of seladelpar.

The entire disclosures of the documents referred to in this applicationare incorporated into this application by reference.

SUMMARY OF THE INVENTION

This invention is a method of treatment of an intrahepatic cholestaticdisease comprising administration of a compound that is seladelpar or asalt thereof in an amount between 0.5 mg/day and 20 mg/day; such as at0.5, 1, or 2 mg/day.

Seladelpar has already been demonstrated to be effective in thetreatment of PBC at doses of 50 mg/day and 200 mg/day. It is alsoeffective in much lower dosages, such as 5 mg/day and 10 mg/day.Similarly, it is expected to be useful in other intrahepatic cholestaticdiseases at similar dosages.

Because seladelpar lowers ALP and GGT, which are elevated inintrahepatic cholestatic diseases, its use will result in a reduction incholestasis and provide an effective treatment for these diseases.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Intrahepatic cholestatic diseases” and their treatment are described inthe subsections entitled “Intrahepatic cholestatic diseases” and“Treatments for intrahepatic cholestatic diseases” of the Background ofthe invention.

“Treating” or “treatment” of an intrahepatic cholestatic disease in ahuman includes one or more of:

-   (1) preventing or reducing the risk of developing an intrahepatic    cholestatic disease, i.e., causing the clinical symptoms of an    intrahepatic cholestatic disease not to develop in a subject who may    be predisposed to an intrahepatic cholestatic disease but who does    not yet experience or display symptoms of the intrahepatic    cholestatic disease (i.e. prophylaxis);-   (2) inhibiting an intrahepatic cholestatic disease, i.e., arresting    or reducing the development of the intrahepatic cholestatic disease    or its clinical symptoms; and-   (3) relieving an intrahepatic cholestatic disease, i.e., causing    regression, reversal, or amelioration of the intrahepatic    cholestatic disease or reducing the number, frequency, duration or    severity of its clinical symptoms.

A “therapeutically effective amount” of seladelpar or a seladelpar saltmeans that amount which, when administered to a human for treating anintrahepatic cholestatic disease, is sufficient to effect treatment forthe intrahepatic cholestatic disease. The therapeutically effectiveamount for a particular subject varies depending upon the age, healthand physical condition of the subject to be treated, the intrahepaticcholestatic disease and its extent, the assessment of the medicalsituation, and other relevant factors. It is expected that thetherapeutically effective amount will fall in a relatively broad rangethat can be determined through routine trial.

“Seladelpar” is described in the subsection entitled “Seladelpar” of theBACKGROUND OF THE INVENTION.

Salts (for example, pharmaceutically acceptable salts) of seladelpar areincluded in this invention and are useful in the methods described inthis application. These salts are preferably formed withpharmaceutically acceptable acids. See, for example, “Handbook ofPharmaceutically Acceptable Salts”, Stahl and Wermuth, eds., VerlagHelvetica Chimica Acta, Zürich, Switzerland, for an extensive discussionof pharmaceutical salts, their selection, preparation, and use. Unlessthe context requires otherwise, reference to seladelpar is a referenceboth to the compound and to its salts.

Because seladelpar contains a carboxyl group, it may form salts when theacidic proton present reacts with inorganic or organic bases. Typicallyseladelpar is treated with an excess of an alkaline reagent, such ashydroxide, carbonate or alkoxide, containing an appropriate cation.Cations such as Na⁺, K⁺, Ca²⁺, Mg²⁺, and NH₄ ⁺ are examples of cationspresent in pharmaceutically acceptable salts. Suitable inorganic bases,therefore, include calcium hydroxide, potassium hydroxide, sodiumcarbonate and sodium hydroxide. Salts may also be prepared using organicbases, such as salts of primary, secondary and tertiary amines,substituted amines including naturally-occurring substituted amines, andcyclic amines, including isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and the like. As noted in the “Seladelpar”subsection, seladelpar is currently formulated as its L-lysine dihydratesalt.

“Comprising” or “containing” and their grammatical variants are words ofinclusion and not of limitation and mean to specify the presence ofstated components, groups, steps, and the like but not to exclude thepresence or addition of other components, groups, steps, and the like.Thus, “comprising” does not mean “consisting of”, “consistingsubstantially of”, or “consisting only of”; and, for example, aformulation “comprising” a compound must contain that compound but alsomay contain other active ingredients and/or excipients.

Formulation and Administration

Seladelpar may be administered by any route suitable to the subjectbeing treated and the nature of the subject's condition. Routes ofadministration include administration by injection, includingintravenous, intraperitoneal, intramuscular, and subcutaneous injection,by transmucosal or transdermal delivery, through topical applications,nasal spray, suppository and the like or may be administered orally.Formulations may optionally be liposomal formulations, emulsions,formulations designed to administer the drug across mucosal membranes ortransdermal formulations. Suitable formulations for each of thesemethods of administration may be found, for example, in “Remington: TheScience and Practice of Pharmacy”, 20th ed., Gennaro, ed., LippincottWilliams & Wilkins, Philadelphia, Pa., U.S.A. Because seladelpar isorally available, typical formulations will be oral, and typical dosageforms will be tablets or capsules for oral administration. As mentionedin the “Seladelpar” subsection, seladelpar has been formulated incapsules for clinical trials.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, preferably in unit dosage form suitable for single administrationof a precise dosage. In addition to an effective amount of seladelpar,the compositions may contain suitable pharmaceutically-acceptableexcipients, including adjuvants which facilitate processing of theactive compounds into preparations which can be used pharmaceutically.“Pharmaceutically acceptable excipient” refers to an excipient ormixture of excipients which does not interfere with the effectiveness ofthe biological activity of the active compound(s) and which is not toxicor otherwise undesirable to the subject to which it is administered.

For solid compositions, conventional excipients include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talc, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. Liquid pharmacologically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in water or an aqueous excipient, such as, for example, water,saline, aqueous dextrose, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliaryexcipients such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc.

For oral administration, the composition will generally take the form ofa tablet or capsule; or, especially for pediatric use, it may be anaqueous or nonaqueous solution, suspension or syrup. Tablets andcapsules are preferred oral administration forms. Tablets and capsulesfor oral use will generally include one or more commonly used excipientssuch as lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. When liquid suspensions are used,the active agent may be combined with emulsifying and suspendingexcipients. If desired, flavoring, coloring and/or sweetening agents maybe added as well. Other optional excipients for incorporation into anoral formulation include preservatives, suspending agents, thickeningagents, and the like.

Typically, a pharmaceutical composition of seladelpar, or a kitcomprising compositions of seladelpar, is packaged in a container with alabel, or instructions, or both, indicating use of the pharmaceuticalcomposition or kit in the treatment of an intrahepatic cholestaticdisease.

A suitable (i.e. a therapeutically effective) amount of seladelpar or asalt thereof for oral dosing, when the amount is calculated asseladelpar, is expected to be at least 0.5 mg/day, for example at least1 mg/day, such as at least 2 mg/day; but not more than 25 mg/day, forexample not more than 15 mg/day, or not more than 10 mg/day; for example1 mg/day, 2 mg/day, 5 mg/day, or 10 mg/day, for an adult subject with anintrahepatic cholestatic disease, depending on the extent and severityof the disease and stage of disease, and factors such as hepatic andrenal function. That is, a suitable amount of seladelpar for oral dosingfor adults in diseases such as PSC and PBC is expected to be below thelow end of the amounts employed in Example 1 but include the amountsemployed in Example 2. Suitable reductions in dose toward or below thelower end of the outer range above may be made for subjects who arechildren in diseases such as PFIC and AS, depending on such additionalfactors as age and body mass; and in subjects with significant hepaticimpairment, such as subjects in Child-Pugh classes B and C [see, forexample, the Wikipedia article “Child-Pugh Score”,https://en.wikipedia.org/wiki/Child-Pugh_score], depending on the degreeof impairment, because a study has suggested a significant increase inthe maximum plasma concentration of seladelpar and an increase in thearea-under-the-curve exposure for seladelpar and two of its threeprincipal metabolites in these groups. These amounts represent anaverage daily dose, and not necessarily an amount given at a singledose. Dosing may be as frequent as more than once/day (where the amount,or daily dose, will be divided between the number of administrations perday), but will more typically be once/day (where the amount is given ina single administration). Optionally, particularly in cases ofsignificant hepatic impairment, the dosing may be less frequent thanonce/day, such as between once/week and every other day, for exampleonce/week, twice/week (especially with the doses at least three daysapart), three times/week (especially with the doses at least two daysapart), or every other day; so that, as an example, a subject mayreceive 5 mg twice/week for an amount (daily dose) of 1.4 mg/day.

A person of ordinary skill in the art of the treatment of intrahepaticcholestatic disease will be able to ascertain a therapeuticallyeffective amount of seladelpar or a seladelpar salt for a particulardisease, stage of disease, and patient to achieve a therapeuticallyeffective amount without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application.

EXAMPLES Example 1: High Dose Trial in PBC (NCT02609048)

The trial subjects were adult, male or female, with a diagnosis of PBCby at least two of the following three criteria: (a) a history ofalkaline phosphatase (ALP) above the upper limit of normal (ULN) for atleast six months, (b) positive anti-mitochondrial antibody titers >1/40on immunofluorescence or M2 positive by enzyme linked immunosorbentassay or positive PBC-specific antinuclear antibodies, and (c)documented liver biopsy result consistent with PBC, on a stable andrecommended dose of UDCA for the past twelve months or UDCA intolerant,and ALP≥1.67×ULN. Exclusion criteria included AST or ALT≥3×ULN, totalbilirubin (TBIL)≥2×ULN, autoimmune hepatitis or a history of chronicviral hepatitis, PSC, the current use of fibrates or simvastatin, theuse of colchicine, methotrexate, azathioprine, or systemic steroids inthe previous two months, the use of an experimental treatment for PBC,and the use of an experimental or unapproved immunosuppressant. Theprimary study endpoint was decrease in ALP, and the secondary endpointwas the responder rate for subjects achieving ALP<1.67×ULN and totalbilirubin within normal limit, and >15% decrease in ALP. Additionalsecondary endpoints were changes in GGT, TBIL, and 5′-nucleotidase,which are other recognized biochemical markers of cholestasis. Subjectswere randomized to receive either placebo, 50 mg/day, or 200 mg/day ofseladelpar as the L-lysine dihydrate salt orally once/day in capsuleform for 12 weeks. During the study, three cases of asymptomaticincreases in transaminases were observed (two in the 200 mg and one inthe 50 mg groups). All three were reversible on cessation of treatmentand were not accompanied by elevation of TBIL. Since the study hadalready shown a clear efficacy signal, the study was discontinued. Afterthe study was unblinded, changes in the primary endpoint ALP wereanalyzed using data available for the 26 subjects (10 in the placebogroup, 9 in the 50 mg/day seladelpar group, and 7 in the 200 mg/dayseladelpar group) enrolled in the study and completing at least twoweeks of treatment. According to the original statistical plan, changesin ALP were calculated using the last observation carried forward. Themean decreases from baseline in ALP for the 50 mg/day and 200 mg/daydose groups were 57% and 62%, respectively, compared with 0.37% forplacebo (p <0.0001 for both). The responder rates for the placebo, 50mg/day, and 200 mg/day groups were 10%, 67% and 100%, respectively,despite the baseline ALP levels being different at 239, 313, and 280U/L. The p-values comparing the responder rates for the 50 mg/day and200 mg/day groups with placebo were 0.020 and 0.0004 (Fisher's ExactTest), respectively. Thus, seladelpar exhibits a rapid and potentanti-cholestatic effect in subjects with PBC. The lack of a doseresponse suggested that lower doses could be effective as well. Since arecently completed preclinical study with seladelpar showed that themain route of elimination of the drug is through bile and that the drugis concentrated in bile, and since subjects with PBC have impaired bileflow, the exposure of the drug to the liver in subjects with PBC couldhave been higher than in prior clinical studies in subjects with normalliver function, explaining both the more potent anticholestatic effectand the transaminase effects. The subjects receiving seladelpar alsodemonstrated improvements in metabolic parameters, including reductionsof LDL-C of 16 and 26% for the 50 mg/day and 200 mg/day dose groups,respectively, vs. 0.8% for placebo after two weeks of dosing. It is alsonoteworthy that, despite the potent anti-cholestatic effect, no adverseevents of pruritus were reported on treatment.

Example 2: Low-Dose Trial in PBC (NCT02955602)

This example describes a study like that of Example 1, but using dosesof 2, 5, or 10 mg/day of seladelpar as the L-lysine dihydrate saltorally once/day in capsule form. In the main study, running for 12weeks, subjects were to receive either 2, 5, or 10 mg/day; while in anextension study, running for an additional 40 weeks, subjects in the 2mg/day group were allowed to continue at the 2 mg/day dose or shift toeither 5 or 10 mg/day, subjects in the 5 mg/day group were allowed tocontinue at the 5 mg/day dose or shift to 10 mg/day, and subjects in the10 mg/day group were allowed to continue at the 10 mg/day dose or shiftto 5 mg/day. At baseline (the mean of the screening values and the valueat day 1), the subjects had the following values, with numbers inparentheses denoting standard deviations:

Normal Population range 2 mg 5 mg 10 mg N 11 30 30 Age, years 55 (10) 57(8)  56 (9)  Sex, F/M 11/0 30/0 27/3 BMI, Kg/m² 29 (7)  27 (7)  26 (5) History of pruritus  7 19 22 ALP (U/L) 37-116 300 (121) 310 (152) 265(83)  GGT (U/L) 7-38 255 (143) 201 (141) 254 (185) ALT (U/L) 6-41 54(25) 40 (22) 49 (25) TBIL (mg/dL) 0.1-1.1  0.60 (0.12) 0.68 (0.35) 0.84(0.34) Albumin (g/dL) 3.5-5.5  4.1 (0.2) 4.0 (0.4) 4.1 (0.3) UDCA dose,mg/Kg 14 (4)  15 (3)  17 (6) 

The study has now been analyzed through 26 weeks: the 12 weeks of themain study and 14 weeks of the extension study.

The week 12 cohort consisted of 6 subjects in the 2 mg/day group, 25subjects in the 5 mg/day group, and 22 subjects in the 10 mg/day group.The mean reduction in ALP at 12 weeks was 21% for the 2 mg/day group,33% for the 5 mg/day group, and 45% for the 10 mg/day group. The meanreduction in ALT at 12 weeks was 9% for the 2 mg/day group, 28% for the5 mg/day group, and 35% for the 10 mg/day group.

The week 26 cohort consisted of 4 subjects in the 2 or 2 to 5 mg/daygroup, 13 subjects in the 5 mg/day group, 6 subjects in the 5 to 10mg/day group, and 19 subjects in the 10 mg/day group. The mean reductionin ALP at 26 weeks was 45% for the 5 mg/day group, 43% for the 5 to 10mg/day group, and 43% for the 10 mg/day group. At 26 weeks, combiningthe 5 mg/day and 5 to 10 mg/day groups into a single group for analysis,there were 19 subjects in the combined group and 19 in the 10 mg/daygroup. Of the combined group, 13 (68%) had ALP≤1.67×ULN, 18 (95%) had adecrease in ALP of ≥15%, and 18 (95%) had TBIL≤ULN, while 5 (26%) hadALP≤ULN. Of the 10 mg/day group, 15 (79%) had ALP≤1.67×ULN, 17 (89%) hada decrease in ALP of≥15%, and 17 (89%) had a TBIL≤ULN, while 6 (32%) hadALP≤ULN. The mean reduction in ALT at 26 weeks was 40% for the combinedgroup and 43% for the 10 mg/day group.

As of the analysis, there had been 6 serious adverse events, all deemedunrelated to seladelpar, and 2 adverse events leading to seladelpardiscontinuation, both deemed unrelated to seladelpar. No transaminasesafety signals, and no signals for drug-induced pruritus, were seen.

Example 3: Trial in PSC

Adult subjects with an intrahepatic cholestatic disease such as PSC aretreated orally with doses of 1, 2, 5, and 10 mg/day of seladelpar.Subjects are permitted their usual other medications, including UDCA.The subjects are assessed before the study, and at intervals during thestudy, such as every 4 weeks during the study and 4 weeks after the lastdose of the seladelpar therapy, for safety and pharmacodynamicevaluations. At each visit, after a 12-hour fast, blood is drawn andurine collected; and a standard metabolic panel, complete blood count,and standard urinalysis are performed. Blood is analyzed for TC, HDL-C,TG, VLDL-C, LDL-C, and apolipoprotein B, for liver function markers suchas total and bone-specific ALP, for GGT, and also for total andconjugated bilirubin. The subjects also maintain health diaries, whichare reviewed at each visit. The subjects show an improvement in theirdisease, as manifested by, for example, a decrease in ALP and GGT.

While this invention has been described in conjunction with specificembodiments and examples, it will be apparent to a person of ordinaryskill in the art, having regard to that skill and this disclosure, thatequivalents of the specifically disclosed materials and methods willalso be applicable to this invention; and such equivalents are intendedto be included within the following claims.

What is claimed is:
 1. A method of treating an intrahepatic cholestatic disease by administering a therapeutically effective amount of a compound that is seladelpar or a salt thereof, where the amount is between 0.5 mg/day and 2 mg/day when the amount of the compound is calculated as seladelpar.
 2. The method of claim 1 where the compound is seladelpar L-lysine dihydrate salt.
 3. The method of claim 1 where the compound is administered orally.
 4. The method of claim 1 where the amount of the compound is 0.5 mg/day, 1 mg/day, or 2 mg/day.
 5. The method of claim 4 where the amount of the compound is 0.5 mg/day.
 6. The method of claim 4 where the amount of the compound is 1 mg/day.
 7. The method of claim 4 where the amount of the compound is 2 mg/day.
 8. The method of claim 1 where the compound is administered once/day.
 9. The method of claim 1 where the compound is administered between once/week and every other day.
 10. The method of claim 1 where the intrahepatic cholestatic disease is primary biliary cholangitis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, or Alagille syndrome.
 11. The method of claim 10 where the intrahepatic cholestatic disease is progressive familial intrahepatic cholestasis.
 12. The method of claim 10 where the intrahepatic cholestatic disease is Alagille syndrome. 